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Drug-inducible and simultaneous regulation of endogenous genes by single-chain nuclear receptor-based zinc-finger transcription factor gene switches

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Overview

authors

  • Magnenat, L.
  • Schwimmer, L. J.
  • Barbas III, Carlos

publication date

  • 2008

journal

  • Gene Therapy  Journal

abstract

  • Chemically inducible gene switches that regulate expression of endogenous genes have multiple applications for basic gene expression research and gene therapy. Single-chain zinc-finger transcription factors that utilize either estrogen receptor homodimers or retinoid X receptor-alpha/ecdysone receptor heterodimers are shown here to be effective regulators of ICAM-1 and ErbB-2 transcription. Using activator (VP64) and repressor (Krüppel-associated box) domains to impart regulatory directionality, ICAM-1 was activated by 4.8-fold and repressed by 81% with the estrogen receptor-inducible transcription factors. ErbB-2 was activated by up to threefold and repressed by 84% with the retinoid X receptor-alpha/ecdysone receptor-inducible transcription factors. The dynamic range of these proteins was similar to the constitutive system and showed negligible basal regulation when ligand was not present. We have also demonstrated that the regulation imposed by these inducible transcription factors is dose dependent, sustainable for at least 11 days and reversible upon cessation of drug treatment. Importantly, these proteins can be used in conjunction with each other with no detectable overlap of activity enabling concurrent and temporal regulation of multiple genes within the same cell. Thus, these chemically inducible transcription factors are valuable tools for spatiotemporal control of gene expression that should prove valuable for research and gene therapy applications.

subject areas

  • Blotting, Western
  • Cell Line, Tumor
  • Flow Cytometry
  • Gene Expression
  • Gene Expression Regulation
  • Genes, Regulator
  • Genes, erbB-2
  • Genetic Engineering
  • Genetic Therapy
  • Humans
  • Intercellular Adhesion Molecule-1
  • Promoter Regions, Genetic
  • Receptors, Cell Surface
  • Transcription Factors
  • Transcription, Genetic
  • Zinc Fingers
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Identity

PubMed Central ID

  • PMC2705884

International Standard Serial Number (ISSN)

  • 0969-7128

Digital Object Identifier (DOI)

  • 10.1038/gt.2008.96

PubMed ID

  • 18528430
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Additional Document Info

start page

  • 1223

end page

  • 1232

volume

  • 15

issue

  • 17

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